Method and Composition for Administering an NMDA Receptor Antagonist to a Subject

ABSTRACT

The invention provides methods and compositions for administering an NMDA receptor antagonist (e.g., memantine) to a subject.

RELATED APPLICATIONS

This application claims priority to U.S. Ser. No. 60/630,885, filed Nov.23, 2004, U.S. Ser. No. 60/701,857, filed Jul. 22, 2005, and U.S. Ser.No. 60/635,365, filed Dec. 10, 2004. The contents of these applicationsare incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compositions containing N-methyl-D-Aspartatereceptor (NMDAr) antagonists and methods for using such compositions.

BACKGROUND OF THE INVENTION

Acute and chronic neurological and neuropsychiatric diseases are amongthe leading causes of death, disability, and economic expense in theworld. One of the key challenges in treating these disorders is the highdegree of interplay amongst the pathways that control both normal andabnormal neuronal function.

Excitatory amino acid receptors, including the N-Methyl-D-Aspartate(NMDA) receptor, are important mediators of excitatory synaptictransmissions (i.e., stimulation of neurons) in the brain, participatingin wide-ranging aspects of both normal and abnormal central nervoussystem (CNS) function. The NMDA receptor and its associated calcium(Ca2+) permeable ion channel are activated by glutamate, a commonexcitatory neurotransmitter in the brain and the spinal cord, and theco-agonist glycine. NMDA receptor (NMDAr) activity and consequent Ca2+influx are necessary for long-term potentiation (a correlate of learningand memory).

Aberrant glutamate receptor activity has been implicated in a largenumber of CNS-related conditions including, for example, depression andother neuropsychiatric conditions, Parkinson's disease, epilepsy, pain,ALS (amyotrophic lateral sclerosis or Lou Gehrig's disease), andHuntington's disease. In such conditions, the abnormal activation of theNMDA receptor resulting from elevated levels of glutamate may lead tosustained activity of the receptor's ion channel (often lasting forminutes rather than milliseconds), thereby allowing Ca2+ to build-up.This creates both symptomatic and neuro-destructive effects on apatient.

Certain NMDAr antagonists, such as memantine and amantadine, readilycross the blood-brain barrier, achieving similar concentrations in theextra cellular fluid surrounding brain tissue and systemic serum.Ideally, NMDAr antagonists should be present at a concentrationsufficient to reduce the symptoms or damaging effects of the disease inthe absence of debilitating side effects. In the present dosage formshowever, these drugs, despite having a relatively long half-lives, needto be administered frequently and require dose escalation at theinitiation of therapy to avoid side effects associated with initialexposure to the therapeutic agent. This leads to difficulty in achievingadequate patient compliance, which is further exacerbated by thecomplicated dosing schedules of therapeutic modalities used forneurological or neuropsychiatric disorders.

Thus, better methods and compositions are needed to treat and delay theprogression of neurological disorders.

SUMMARY OF THE INVENTION

In general, the present invention provides pharmaceutical compositionsthat are administered so as to deliver to a subject, an amount of anNMDAr antagonist that is high enough to treat symptoms or damagingeffects of an underlying disease while avoiding undesirable sideeffects, particularly CNS side effects. These compositions may beemployed to administer the NMDAr antagonist at a lower frequency thanpresently employed (i.e., once a day (q.d.) versus twice a day (b.i.d)or three times a day (t.i.d)), improving patient compliance andcaregiver convenience. These compositions are particularly useful asthey provide the NMDAr antagonist at a therapeutically effective amountfrom the onset of therapy further improving patient compliance andadherence and enable the achievement of a therapeutically effectivesteady-state concentration of the NMDAr antagonist in a shorter periodof time. This results in an earlier indication of effectiveness andincreasing the utility of these therapeutic agents for diseases andconditions where time is of the essence. Furthermore, the compositionsof the present invention, by virtue of their design, allow for higherdoses of NMDAr antagonist to be safely administered, again increasingthe utility of these agents for a variety of indications. Also providedare methods for making, dosing and using such compositions.

The NMDAr antagonist is desirably provided in a controlled or extendedrelease form, with or without an immediate release component in order tomaximize the therapeutic benefit of the NMDAr antagonist, while reducingunwanted side effects. In the absence of modified release components(referred to herein as controlled, extended or delayed releasecomponents), the NMDAr antagonist is released and transported into thebody fluids over a period of minutes to several hours. In a preferredembodiment, the composition of the invention contains an NMDArantagonist and a sustained release component, such as a coated sustainedrelease matrix, a sustained release matrix, or a sustained release beadmatrix. In one example, memantine (e.g., 5-80 mg) is formulated withoutan immediate release component using a polymer matrix (e.g., Eudragit),Hydroxypropyl methyl cellulose (HPMC) and a polymer coating (e.g.,Eudragit). Such formulations are compressed into solid tablets orgranules and coated with a controlled release material such as Opadry®or Surelease®.

NMDAr Antagonists.

The NMDAr antagonist may be an aminoadamantine derivative such asmemantine (1-amino-3,5-dimethyladamantane), rimantadine(1-(1-aminoethyl)adamantane), or amantadine (1-amino-adamantane) as wellas others described below.

Excipients

The excipients used to produce the formulation may include bulkingagents, lubricants, glidants, and release controlling agents. Many suchmaterials are found in “Remington: The Science and Practice of Pharmacy,Twentieth Edition,” Lippincott Williams & Wilkins, Philadelphia, Pa. andcommonly known to the skilled artisan. The specific excipients used willbe determined by the requirements for administration of the dosage,including the targeted dosing frequency, slope of drug release andabsorption, and route of administration. In one embodiment, theformulation does not contain a casein salt.

Dosage Form

The NMDAr antagonist may be formulated as a suspension, capsule, tablet,suppository, lotion, patch, or device (e.g., a subdermally implantabledelivery device or an inhalation pump). In preferred embodiments, thedosage form is provided for oral administration, e.g. as a capsule.

Release Profile

The compositions described herein are formulated such the NMDArantagonist has an in vitro dissolution profile that is slower than thatfor an immediate release (IR) formulation. As used herein, the immediaterelease (IR) formulation for memantine means the present commerciallyavailable 5 mg and 10 mg tablets (i.e., Namenda from ForestLaboratories, Inc. or formulations having substantially the same releaseprofiles as Namenda); and for the immediate release (IR) formulation ofamantadine means the present commercially available 100 mg tablets(i.e., Symmetrel from Endo Pharmaceuticals, Inc. or formulations havingsubstantially the same release profiles as Symmetrel). Thesecompositions may contain immediate release, sustained or extendedrelease, delayed release components, or combinations thereof. Thus, thepresent compositions may be formulated such that the fraction of theNMDAr antagonist released is greater or equal to0.01(0.297+0.0153*e^((0.515)*^(t))) and less than 1−e^((−10.9)*^(t)), asmeasured using a USP type 2 (paddle) dissolution system at 50 rpm, at atemperature of 37±0.5° C., in water, where t is the time in hours and tis greater than zero and equal or less than 17. Thus, the fraction ofNMDAr antagonist that is released is less than 93% in 15 minutes and7.7%-100% in 12 hours using a USP type 2 (paddle) dissolution system at50 rpm, at a temperature of 37±0.5° C. in a neutral pH (e.g. water orbuffered aqueous solution) or acidic (e.g. 0.1 N HCl) dissolutionmedium. Optionally, the fraction of released NMDAr antagonist is greateror equal to 0.01(0.297+0.0153*e^((0.515)*^(t))) and less than or equalto 1−e^((−0.972)*^(t)) as measured using a USP type 2 (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C., in water,where t is the time in hours and t is greater than zero and equal orless than 17. Optionally, the fraction of released NMDAr antagonist isgreater or equal to 0.01(−2.75+2.75*e^((0.21)*^(t))) and less than orequal to 1−e^((−0.40)*^(t)) as measured using a USP type 2 (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C., in water,where t is the time in hours and t is greater than zero and equal orless than 17. Thus, the fraction of NMDAr antagonist that is releasedmay range between 0.1%-62% in one hour, 0.2%-86% in two hours, 0.6%-100%in six hours, 2.9%-100% in 10 hours, and 7.7%-100% in 12 hours using aUSP type 2 (paddle) dissolution system at 50 rpm, at a temperature of37±0.5° C. in a neutral pH (e.g. water or buffered aqueous solution) oracidic (e.g. 0.1 N HCl) dissolution medium. Optionally, the fraction ofNMDAr antagonist that is released may range between 0.6%-33% in onehour, 1.4%-55% in two hours, 6.9%-91% in six hours, 19.7%-98% in 10hours, and 31%-100% in 12 hours using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C. in a neutral pH (e.g.water or buffered aqueous solution) or acidic (e.g. 0.1 N HCl)dissolution medium. Optionally, the NMDA receptor antagonist has arelease profile ranging between 0.1%-20% in one hour, 5%-30% in twohours, 40%-80% in six hours, 70% or greater (e.g., 70%-90%) in 10 hours,and 90% or greater (e.g., 90-95%) in 12 hours as measured in adissolution media having a neutral pH (e.g. water or buffered aqueoussolution) or in an acidic (e.g. 0.1 N HCl) dissolution medium. Forexample, a formulation containing memantine may have a release profileranging between 0-60% or 0.1-20% in one hour, 0-86% or 5-30% at twohours, 0.6-100% or 40-80% at six hours, 3-100% or 50% or more (e.g.,50-90%) at ten hours, and 7.7-100% at twelve hours in a dissolutionmedia having a neutral pH (e.g. water or buffered aqueous solution) orin an acidic (e.g. 0.1 N HCl) dissolution medium.

In one embodiment, the NMDAr antagonist has an in vitro dissolutionprofile of less than 25%, 15%, 10%, or 5% in fifteen minutes; 50%, 30%,25%, 20%, 15%, or 10% in 30 minutes and more than 60%, 65% 70%, 75%,80%, 85%, 90%, 95% at 16 hours as obtained using a USP type II (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C. in water.Desirably, the NMDAr antagonist has a dissolution of at least 65%, 70%,75%, 80%, 85%, 90%, or 95% in a dissolution media having a pH of 1.2 at10 hours.

Desirably, the compositions described herein have an in vitro profilethat is substantially identical to the dissolution profile shown inFIGS. 2A-2C and, upon administration to a subject at a substantiallyconstant daily dose, achieves a serum concentration profile that issubstantially identical to that shown in FIG. 2D.

Initial Rate of Release In Vivo

As used herein, “C” refers to the concentration of an activepharmaceutical ingredient in a biological sample, such as a patientsample (e.g. blood, serum, and cerebrospinal fluid). The concentrationof the drug in the biological sample may be determined by any standardassay method known in the art. The term “Cmax” refers to the maximumconcentration reached by a given dose of drug in a biological sample.The term “Cmean” refers to the average concentration of the drug in thesample over time. Cmax and Cmean may be further defined to refer tospecific time periods relative to administration of the drug. The timerequired to reach the maximal concentration (“Cmax”) in a particularpatient sample type is referred to as the “Tmax”. The change inconcentration is termed “dC” and the change over a prescribed time is“dC/dT”.

Desirably, the NMDAr antagonist is released into a subject sample at aslower rate than observed for an immediate release (IR) formulation ofthe same quantity of the antagonist, such that the rate of change in thebiological sample measured as the dC/dT over a defined period within theperiod of 0 to Tmax for the IR formulation and the dC/dT rate is lessthan about 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate for theIR formulation (e.g., Namenda, a commercially available IR formulationof memantine). In some embodiments, the dC/dT rate is less than about80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate for the IRformulation. Similarly, the rate of release of the NMDAr antagonist fromthe present invention as measured in dissolution studies is less than80%, 70%, 60% 50%, 40%, 30%, 20%, or 10% of the rate for an IRformulation of the same NMDAr antagonist over the first 1, 2, 4, 6, 8,10, or 12 hours.

In a preferred embodiment, the dosage form is provided in a non-doseescalating, twice per day or once per day form. In such cases, theconcentration ramp (or Tmax effect) may be reduced so that the change inconcentration as a function of time (dC/dT) is altered to reduce oreliminate the need to dose escalate the drug. A reduction in dC/dT maybe accomplished, for example, by increasing the Tmax in a relativelyproportional manner. Accordingly, a two-fold increase in the Tmax valuemay reduce dC/dT by approximately a factor of 2. Thus, the NMDArantagonist may be provided so that it is released at a rate that issignificantly reduced over an immediate release (so called IR) dosageform, with an associated delay in the Tmax. The pharmaceuticalcomposition may be formulated to provide a shift in Tmax by 24 hours, 16hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. The associatedreduction in dC/dT may be by a factor of approximately 0.05, 0.10, 0.25,0.5 or at least 0.8. In certain embodiments, this is accomplished byreleasing less than 30%, 50%, 75%, 90%, or 95% of the NMDAr antagonistinto the circulatory or neural system within one hour of suchadministration.

Optionally, the modified release formulations exhibit plasmaconcentration curves having initial (e.g., from 2 hours afteradministration to 4 hours after administration) slopes less than 75%,50%, 40%, 30%, 20% or 10% of those for an IR formulation of the samedosage of the same NMDAr antagonist. The precise slope for a givenindividual will vary according to the NMDAr antagonist being used, thequantity delivered, or other factors, including, for some activepharmaceutical agents, whether the patient has eaten or not. For otherdoses, e.g., those mentioned above, the slopes vary directly inrelationship to dose.

Using the sustained release formulations or administration methodsdescribed herein, the NMDAr antagonist reaches a therapeuticallyeffective steady state plasma concentration in a subject within thecourse of the first three, five, seven, nine, ten, twelve, fifteen, ortwenty days of administration. For example, the formulations describedherein, when administered at a substantially constant daily dose (e.g.,at a dose ranging between 15 mg and 80 mg, preferably between 20 mg and65 mg, and more preferably between 20 mg and 45 mg per day) may reach asteady state plasma concentration in approximately 70%, 60%, 50%, 40%,30%, or less of the time required to reach such plasma concentrationwhen using a dose escalating regimen.

Reduced Cmax, Extented Tmax

In a preferred embodiment of this invention, at least 75%, 90%, 95%,97%, 98%, 99% or even 100% of the NMDAr antagonist is provided in amodified or extended release dosage form and upon the administration ofthis composition to a subject (e.g., a mammal such as a human), theNMDAr antagonist has a Cmax/C mean of approximately 2.5, 2, 1.5, or 1.0,approximately 1, 1.5, 2 hours to at least 6, 9, 12, 18, 21, 24 hoursfollowing such administration. If desired, the release of the NMDArantagonist may be monophasic or multiphasic (e.g., biphasic). Desirably,99%, 98%, 95%, 90%, 85%, 80%, 70%, 50%, or 30% of the NMDAr antagonistremains in an extended release dosage form within one hour of suchadministration.

Dosing Frequency Reduction

The compositions and methods of the instant invention also enable areduction in the dosing frequency. For example, an NMDAr antagonistordinarily administered two to four times per day when dosing in an IRform may be provided to the subject once or twice per day using theformulations described herein. In some embodiments, the compositionsdescribed herein are administered even less frequently, e.g. every 2days, every 3 days, every week, or every month.

Non-Dose Escalation

Immediate release (IR) formulations of NMDAr antagonists are typicallyadministered in a dose-escalating fashion, frequently starting withsubtherapeutic amounts of the agent. Although dosing adjustments orindividualization may be managed by a physician for a pharmaceuticalcomposition the compositions described herein may be administered at anessentially constant, therapeutically-effective dose from the initiationof therapy, thereby improving patient and caregiver compliance,adherence, and convenience.

Furthermore, the compositions described herein enable the use of higherdoses of NMDAr antagonist equal or fewer adverse effects than observedfor IR formulations of the same agent, increasing the utility of theNMDAr antagonist for indications described herein.

Reduced Time to Therapeutic Concentration and Efficacy

The administration of the compositions described herein attherapeutically effective doses from the initiation of therapy enablesthe attainment of a steady state level of the agent in a shorter timeperiod (e.g. 20%, 30%, 50%, 70%, 90% less time than for dose-escalatedregimens), thus enabling the treatment of more acute disorders such aspain and neuropsychiatric disorders, including depression, agitation,bipolar disorder, and drug dependency, withdrawal, or tolerance.

Conditions Amenable to Treatment

The compositions of the present invention may be employed to treat orreduce the symptoms associated with deregulation in NMDA receptoractivity or conditions that would benefit from a reduction in suchactivity. Further, many NMDAr antagonists have other known activities(e.g. the dopaminergic activity of amantadine, the antiviral activity ofrimantadine). The compositions of the present invention are also usefulto treat, prevent, or reduce conditions associated with such activitiesin any subject having or at risk of having a such condition. Exemplaryconditions include seizure disorders, pain syndromes, neurodegenerativediseases (including motor neuron diseases, myelopathies,radiculopathies, and disorders of the sympathetic nervous system),dementias, cerebrovascular conditions, movement disorders, brain trauma,cranial nerve disorders, neuropsychiatric disorders, and other diseaseneuropathies (including viral associated neuropathies, diabetesassociated neuropathies, Guillian-Barre syndrome, dysproteinemias,transthyretin-induced neuropathies, and carpal tunnel syndrome).

Alternate Routes of Administration

In one embodiment, the compositions described herein are formulated astablets or capsules for oral administration or patches for transdermaldelivery of the NMDAr antagonist. Alternatively, the compositions may beprepared in other ways for these routes of administration (e.g. as asuspension for oral administration) or specifically for otheradministrative routes intravenous, topical, intranasal, subtopicaltransepithelial, subdermal, or inhalation delivery.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present Specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting. Allparts and percentages are by weight unless otherwise specified.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a graph showing the memantine plasma concentration over aperiod of 24 hours, as predicted by Gastro-Plus software packagev.4.0.2, following the administration of a single dose of an immediaterelease (IR) formulation of memantine (Namenda) or a sustained releaseformulation of memantine (NPI-6701). The sustained release formulationexhibits a dC/dT during the initial phase that is about 20% of that forthe immediate release (IR) formulation.

FIG. 1B is a graph showing the memantine plasma concentration over aperiod of 28 days, as predicted by Gastro-Plus software package v.4.0.2,following the administration of an immediate release (IR) formulation ofmemantine (Namenda) and a sustained release formulation of memantine(NPI-6701). When Namenda is administered using a dose escalation regimenpursuant to the manufacturer's US FDA approved label, a steady-statetherapeutically effective plasma concentration is reached within about30 days. The administration of a sustained release formulation ofmemantine at a constant dose (e.g., 22.5 mg/day) achieves a steadytherapeutically effective plasma concentration within about 13 days, areduction of about 60%.

FIG. 2A is a graph and a table showing the in vitro dissolution profilesfor various sustained release formulations of memantine (NPI-6601,NPI-6701, NPI-6801, NPI-6990, and NPI-6804) and Namenda. Dissolutionprofiles were obtained with a USP II (Paddle) system using water as adissolution medium.

FIG. 2B is a graph showing the dissolution profiles for varioussustained release formulations of memantine (NPI-6601, NPI-6701,NPI-6801, NPI-6990, and NPI-6804) and Namenda obtained with a USP II(Paddle) system using 0.1N hydrochloride solution pH=1.2 as thedissolution medium.

FIG. 2C is a graph showing the dissolution profile of memantineformulated as a sustained release form using a neutral (e.g., water) andacidic (pH 1.2) dissolution medium.

FIG. 2D is a graph and table showing the memantine plasma concentrationover a period of 24 hours, as predicted by Gastro-Plus software packagev.4.0.2, following the administration of Namenda (10 mg b.i.d. or singledose of 20 mg) or various sustained release formulations of memantine(i.e., NPI-6601, NPI-6701, NPI-6801, NPI-6804, and NPI-6990 administeredat a single dose of 22.5 mg).

FIG. 3A is a graph and table showing the dissolution profiles forvarious sustained released memantine bead/capsule formulations. Theexperimental dissolution profiles were obtained from a USP II Paddlesystem using water (pH=7) as the medium.

FIG. 3B is a graph and table showing the predicted dissolution profilefor a simple two-bead composite capsule (13% of 5001-6991 & 87% of5001-6992).

FIG. 4 is a graph showing dissolution profiles for modified releaseformulations of memantine and an IR formulation of memantine (Namenda).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

In general, the present invention features pharmaceutical compositionsthat contain an NMDAr antagonist formulated for extended or modifiedrelease to provide a serum or plasma concentration over a desired timeperiod that is high enough to be therapeutically effective but at a ratelow enough so as to avoid adverse events associated with the NMDArantagonist. Control of drug release is particularly desirable forreducing and delaying the peak plasma level while maintaining the extentof drug bioavailability. Therapeutic levels are therefore achieved whileminimizing debilitating side-effects that are usually associated withimmediate release formulations. Furthermore, as a result of the delay inthe time to obtain peak serum or plasma level and the extended period oftime at the therapeutically effective serum or plasma level, the dosagefrequency is reduced to, for example, once or twice daily dosage,thereby improving patient compliance and adherence. For example, sideeffects including psychosis and cognitive deficits associated with theadministration of NMDAr antagonists may be lessened in severity andfrequency through the use of controlled-release methods that shift theTmax to longer times, thereby reducing the dC/dT of the drug. Reducingthe dC/dT of the drug not only increases Tmax, but also reduces the drugconcentration at Tmax and reduces the Cmax/Cmean ratio providing a moreconstant amount of drug to the subject being treated over a given periodof time enabling a increased dosages for appropriate indications.

Making NMDAr Antagonist Controlled Release Formulations

A pharmaceutical composition according to the invention is prepared bycombining a desired NMDAr antagonist or antagonists with one or moreadditional ingredients that, when administered to a subject, causes theNMDAr antagonist to be released at a targeted rate for a specifiedperiod of time. A release profile, i.e., the extent of release of theNMDAr antagonist over a desired time, can be conveniently determined fora given time by measuring the release using a USP dissolution apparatusunder controlled conditions. Preferred release profiles are those whichslow the rate of uptake of the NMDAr antagonist in the neural fluidswhile providing therapeutically effective levels of the NMDArantagonist. One of ordinary skill in the art can prepare combinationswith a desired release profile using the NMDAr antagonists andformulation methods described below.

NMDAr Antagonists

Any NMDAr antagonist can be used in the methods and compositions of theinvention, particularly those that are non-toxic when used in thecompositions of the invention. The term “nontoxic” is used in a relativesense and is intended to designate any substance that has been approvedby the United States Food and Drug Administration (“FDA”) foradministration to humans or, in keeping with established regulatorycriteria and practice, is susceptible to approval by the FDA or similarregulatory agency for any country for administration to humans oranimals.

The term “NMDAr antagonist”, as used herein, includes anyamino-adamantane compound including, for example, memantine(1-amino-3,5-dimethyladamantane), rimantadine(1-(1-aminoethyl)adamantane), amantadine (1-amino-adamantane), as wellas pharmaceutically acceptable salts thereof. Memantine is described,for example, in U.S. Pat. Nos. 3,391,142, 5,891,885, 5,919,826, and6,187,338. Amantadine is described, for example, in U.S. Pat. Nos.3,152,180, 5,891,885, 5,919,826, and 6,187,338. Additionalaminoadamantane compounds are described, for example, in U.S. Pat. Nos.4,346,112, 5,061,703, 5,334,618, 6,444,702, 6,620,845, and 6,662,845.All of these patents are hereby incorporated by reference.

Further NMDAr antagonists that may be employed include, for example,amino cyclohexanes (i.e., neramexane), ketamine, eliprodil, ifenprodil,dizocilpine, remacemide, iamotrigine, riluzole, aptiganel,phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine,levemopamil, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and itsmetabolite, dextrorphan ((+)-3-hydroxy-N-methylmorphinan), apharmaceutically acceptable salt, derivatives or ester thereof, or ametabolic precursor of any of the foregoing.

Optionally, the NMDAr antagonist in the instant invention is memantineand not amantadine or dextromethorphan.

Dosing, PK, & Tox

The pharmaceutical composition may be formulated to provide memantine inan amount ranging between 1-200 mg/day, 1 and 80 mg/day, 2-80 mg/day,5-80 mg/day, 5 and 65 mg/day, 5 and 40 mg/day, 15 and 45 mg/day, or 10and 20 mg/day; amantadine in an amount ranging between 15 and 900mg/day, 15 mg and 800 mg/day, 15 mg and 700 mg/day, 15 mg and 600mg/day, 15 and 500 mg/day, 25 and 500 mg/day, 15 and 400 mg/day, 25 and300 mg/day, 100 and 300 mg/day, or 100 and 200 mg/day; dextromethorphanin an amount ranging between 1-5000 mg/day, 1-1000 mg/day, and 100-800mg/day, or 200-500 mg/day. Pediatric doses will typically be lower thanthose determined for adults.

Table 1 shows exemplary the pharmacokinetic properties (e.g., Tmax andT1/2) of memantine, amantadine, and rimantadine.

TABLE 1 Pharmacokinetics and Tox in humans for selected NMDArantagonists Human PK (t½) Tmax Normal Dose Dependent Compound (hours)(hours) Dose Tox Memantine 60 3 10-20 Dose escalation mg/day, required,starting at hallucination 5 mg Amantadine 15 3 100-300 Hallucinationmg/day, starting at 100 mg/day Rimantadine 25 6 100-200 Insomnia mg/day

Excipients

“Pharmaceutically or Pharmacologically Acceptable” includes molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. “Pharmaceutically Acceptable Carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions. “Pharmaceutically AcceptableSalts” include acid addition salts and which are formed with inorganicacids such as, for example, hydrochloric or phosphoric acids, or suchorganic acids as acetic, oxalic, tartaric, mandelic, and the like. Saltsformed with the free carboxyl groups can also be derived from inorganicbases such as, for example, sodium, potassium, ammonium, calcium, orferric hydroxides, and such organic bases as isopropylamine,trimethylamine, histidine, procaine and the like.

The preparation of pharmaceutical or pharmacological compositions areknown to those of skill in the art in light of the present disclosure.General techniques for formulation and administration are found in“Remington: The Science and Practice of Pharmacy, Twentieth Edition,”Lippincott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules,pills, powders, granules, dragées, gels, slurries, ointments, solutionssuppositories, injections, inhalants and aerosols are examples of suchformulations.

By way of example, extended or modified release oral formulation can beprepared using additional methods known in the art. For example, asuitable extended release form of the either active pharmaceuticalingredient or both may be a matrix tablet or capsule composition.Suitable matrix forming materials include, for example, waxes (e.g.,carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids,and fatty alcohols), oils, hardened oils or fats (e.g., hardenedrapeseed oil, castor oil, beef tallow, palm oil, and soya bean oil), andpolymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone,hydroxypropyl methyl cellulose, and polyethylene glycol). Other suitablematrix tabletting materials are microcrystalline cellulose, powderedcellulose, hydroxypropyl cellulose, ethyl cellulose, with othercarriers, and fillers. Tablets may also contain granulates, coatedpowders, or pellets. Tablets may also be multi-layered. Multi-layeredtablets are especially preferred when the active ingredients havemarkedly different pharmacokinetic profiles. Optionally, the finishedtablet may be coated or uncoated.

The coating composition typically contains an insoluble matrix polymer(approximately 15-85% by weight of the coating composition) and a watersoluble material (e.g., approximately 15-85% by weight of the coatingcomposition). Optionally an enteric polymer (approximately 1 to 99% byweight of the coating composition) may be used or included. Suitablewater soluble materials include polymers such as polyethylene glycol,hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such assugars (e.g., lactose, sucrose, fructose, mannitol and the like), salts(e.g., sodium chloride, potassium chloride and the like), organic acids(e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), andmixtures thereof. Suitable enteric polymers include hydroxypropyl methylcellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate,polyvinyl acetate phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, shellac, zein, and polymethacrylates containingcarboxyl groups.

The coating composition may be plasticised according to the propertiesof the coating blend such as the glass transition temperature of themain component or mixture of components or the solvent used for applyingthe coating compositions. Suitable plasticisers may be added from 0 to50% by weight of the coating composition and include, for example,diethyl phthalate, citrate esters, polyethylene glycol, glycerol,acetylated glycerides, acetylated citrate esters, dibutylsebacate, andcastor oil. If desired, the coating composition may include a filler.The amount of the filler may be 1% to approximately 99% by weight basedon the total weight of the coating composition and may be an insolublematerial such as silicon dioxide, titanium dioxide, talc, kaolin,alumina, starch, powdered cellulose, MCC, or polacrilin potassium.

The coating composition may be applied as a solution or latex in organicsolvents or aqueous solvents or mixtures thereof. If solutions areapplied, the solvent may be present in amounts from approximate by25-99% by weight based on the total weight of dissolved solids. Suitablesolvents are water, lower alcohol, lower chlorinated hydrocarbons,ketones, or mixtures thereof. If latexes are applied, the solvent ispresent in amounts from approximately 25-97% by weight based on thequantity of polymeric material in the latex. The solvent may bepredominantly water.

The NMDAr antagonist may be formulated using any of the followingexcipients or combinations thereof.

Excipient name Chemical name Function Avicel PH102 MicrocrystallineCellulose Filler, binder, wicking, disintegrant Avicel PH101Microcrystalline Cellulose Filler, binder, disintegrant Eudragit RS-30DPolymethacrylate Poly(ethyl Film former, tablet binder, tablet diluent;Rate acrylate, nethyl methacrylate, controlling polymer for controlledrelease timethylammonioethyl methacrylate chloride) 1:2:0.1 MethocelK100M Hydroxypropyl Rate controlling polymer for controlled release;Premium CR methylcellulose binder; viscosity-increasing agent MethocelK100M Hydroxypropyl Rate controlling polymer for controlled release;methylcellulose binder; viscosity-increasing agent Magnesium StearateMagnesium Stearate Lubricant Talc Talc Dissolution control;anti-adherent, glidant Triethyl Citrate Triethyl Citrate PlasticizerMethocel E5 Hydroxypropyl methylcellulose Film-former Opadry ®Hydroxypropyl methylcellulose One-step customized coating system whichcombines polymer, plasticizer and, if desired, pigment in a dryconcentrate. Surelease ® Aqueous Ethylcellulose Film-forming polymer;plasticizer and stabilizers. Dispersion Rate controlling polymercoating.

The pharmaceutical composition described herein may also include acarrier such as a solvent, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Pharmaceutically acceptable salts can also be used inthe composition, for example, mineral salts such as hydrochlorides,hydrobromides, phosphates, or sulfates, as well as the salts of organicacids such as acetates, proprionates, malonates, or benzoates. Thecomposition may also contain liquids, such as water, saline, glycerol,and ethanol, as well as substances such as wetting agents, emulsifyingagents, or pH buffering agents. Liposomes, such as those described inU.S. Pat. No. 5,422,120, WO 95/13796, WO 91/14445, or EP 524,968 B1, mayalso be used as a carrier.

Methods for Preparing Modified or Extended Release Formulations

Suitable methods for preparing the compositions described herein inwhich the NMDAr antagonist is provided in extended release-formulationsinclude those described in U.S. Pat. No. 4,606,909 (hereby incorporatedby reference). This reference describes a controlled release multipleunit formulation in which a multiplicity of individually coated ormicroencapsulated units are made available upon disintegration of theformulation (e.g., pill or tablet) in the stomach of the subject (see,for example, column 3, line 26 through column 5, line 10 and column 6,line 29 through column 9, line 16). Each of these individually coated ormicroencapsulated units contains cross-sectionally substantiallyhomogenous cores containing particles of a sparingly soluble activesubstance, the cores being coated with a coating that is substantiallyresistant to gastric conditions but which is erodable under theconditions prevailing in the gastrointestinal tract.

The composition of the invention may alternatively be formulated usingthe methods disclosed in U.S. Pat. No. 4,769,027, for example.Accordingly, extended release formulations involve prills ofpharmaceutically acceptable material (e.g., sugar/starch, salts, andwaxes) may be coated with a water permeable polymeric matrix containingan NMDAr antagonist and next overcoated with a water-permeable filmcontaining dispersed within it a water soluble particulate pore formingmaterial.

The NMDAr antagonist composition may additionally be prepared asdescribed in U.S. Pat. No. 4,897,268, involving a biocompatible,biodegradable microcapsule delivery system. Thus, the NMDAr antagonistmay be formulated as a composition containing a blend of free-flowingspherical particles obtained by individually microencapsulatingquantities of memantine, for example, in different copolymer excipientswhich biodegrade at different rates, therefore releasing memantine intothe circulation at a predetermined rates. A quantity of these particlesmay be of such a copolymer excipient that the core active ingredient isreleased quickly after administration, and thereby delivers the activeingredient for an initial period. A second quantity of the particles isof such type excipient that delivery of the encapsulated ingredientbegins as the first quantity's delivery begins to decline. A thirdquantity of ingredient may be encapsulated with a still differentexcipient which results in delivery beginning as the delivery of thesecond quantity beings to decline. The rate of delivery may be altered,for example, by varying the lactide/glycolide ratio in apoly(D,L-lactide-co-glycolide) encapsulation. Other polymers that may beused include polyacetal polymers, polyorthoesters, polyesteramides,polycaprolactone and copolymers thereof, polycarbonates,polyhydroxybuterate and copolymers thereof, polymaleamides,copolyaxalates and polysaccharides.

Alternatively, the composition may be prepared as described in U.S. Pat.No. 5,395,626, which features a multilayered controlled releasepharmaceutical dosage form. The dosage form contains a plurality ofcoated particles wherein each has multiple layers about a corecontaining an NMDAr antagonist whereby the drug containing core and atleast one other layer of drug active is overcoated with a controlledrelease barrier layer therefore providing at least two controlledreleasing layers of a water soluble drug from the multilayered coatedparticle.

Release Profile (Dissolution Rate)

As described above, the NMDAr antagonist may be provided in a modifiedor extended release form. Extended or modified drug release is generallycontrolled either by diffusion through a coating or matrix or by erosionof a coating or matrix by a process dependent on, for example, enzymesor pH. The NMDAr antagonist may be formulated for extended or modifiedrelease as described herein or using standard techniques in the art. Inone example, at least 50%, 75%, 90%, 95%, 96%, 97%, 98%, 99%, or even inexcess of 99% of the NMDAr antagonist is provided in an extended releasedosage form.

Optionally, the compositions described herein have an in vitro profilethat is substantially identical to the dissolution profile shown inFIGS. 2A-2C and, upon administration to a subject at a substantiallyconstant daily dose, achieves a serum concentration profile that issubstantially identical to that shown in FIG. 2D. The dissolutionprofile of the composition of the invention may be determined using aUSP type 2 (paddle) dissolution system at 50 rpm, at a temperature of37±0.5° C. in various dissolution media. In one example, the releasefraction is greater or equal to 0.01(0.297+0.0153*e^((0.515)*^(t))) andless than 1−e^((−10.9)*^(t)). In another example, the release fractionis greater or equal to 0.01(0.297+0.0153*e^((0.515)*^(t))) and less thanor equal to 1−e^((−0.972)*^(t)). In both examples, the term “t” is thetime in hours and t is greater than zero and equal or less than 17.Thus, the NMDAr antagonist may have an in vitro dissolution profile thatranges between 0.1%-62% in one hour, 0.2%-86% in two hours, 0.6%-100% insix hours, 2.9%-100% in 10 hours, and 7.7%-100% in 12 hours using a USPtype 2 (paddle) dissolution. Optionally, the release profile may rangebetween 0.1%-20% in one hour, 5%-30% in two hours, 40%-80% in six hours,50%-90% in 10 hours, and 90%-95% in 12 hours. Desirably, the NMDArantagonist has an in vitro dissolution profile in a solution with aneutral pH (e.g., water) that is substantially the same as itsdissolution profile in an acidic dissolution medium (see FIGS. 2A-2C).

In one embodiment, the NMDAr antagonist has an in vitro dissolutionprofile of less than 15%, 10%, or 5% in fifteen minutes, 25%, 20%, 15%,or 10% in 30 minutes, and more than 60% at 16 hours as obtained using aUSP type II (paddle) dissolution system at 50 rpm, at a temperature of37±0.5° C. in water. Desirably, the NMDAr antagonist has a dissolutionof at least 65%, 70%, 75%, 80%, 85%, 90%, or 95% at 10 hours in adissolution medium having a pH of 1.2.

Initial Rate In Vivo, Delayed Tmax, Reduced Cmax/Cmean

The NMDAr antagonist is provided as a modified release formulation thatmay or may not contain an immediate release formulation. If desired, theNMDAr antagonist may formulated so that it is released at a rate that issignificantly reduced over an immediate release (IR) dosage form, withan associated delay in the Tmax. The pharmaceutical composition may beformulated to provide a shift in Tmax by 24 hours, 16 hours, 8 hours, 4hours, 2 hours, or at least 1 hour. The associated reduction in dC/dTmay be by a factor of approximately 0.05, 0.10, 0.25, 0.5 or at least0.8. In addition, the NMDAr antagonist may be provided such that it isreleased at rate resulting in a Cmax/C mean of approximately 2 or lessfor approximately 2 hours to at least 8 hours after the NMDAr antagonistis introduced into a subject. Optionally, the sustained releaseformulations exhibit plasma concentration curves having initial (e.g.,from 0, 1, 2 hours after administration to 4, 6, 8 hours afteradministration) slopes less than 75%, 50%, 40%, 30%, 20% or 10% of thosefor an IR formulation of the same dosage of the same NMDAr antagonist.The precise slope for a given individual will vary according to theNMDAr antagonist being used or other factors, including whether thepatient has eaten or not. For other doses, e.g., those mentioned above,the slopes vary directly in relationship to dose. The determination ofinitial slopes of plasma concentration is described, for example, byU.S. Pat. No. 6,913,768, hereby incorporated by reference.

Thus, upon the administration to a subject (e.g., a mammal such as ahuman), the NMDAr antagonist has a Cmax/Cmean of approximately 2.5, 2,1.5, or 1.0 approximately 1, 1.5, 2 hours to at least 6, 8, 9, 12, 18,21, 24 hours following such administration. If desired, the release ofthe NMDAr antagonist may be monophasic or multiphasic (e.g., biphasic).One of ordinary skill in the art can prepare compositions with a desiredrelease profile using the NMDAr antagonists and formulation methodsknown in the art or described below.

Dosing Frequency and Dose Escalation

According to the present invention, a subject (e.g., human) having or atrisk of having such conditions is administered any of the compositionsdescribed herein (e.g., once a day, every 2 days, every 3 days, everyweek, or every month). While immediate formulations of NMDAr antagonistsare typically administered in a dose-escalating fashion, thecompositions described herein may be essentially administered at aconstant, therapeutically-effective dose over a set period of time. Forexample, a composition containing a sustained release formulation ofmemantine may be administered twice a day, once a day, once every twodays, or once every three days in a unit dose containing 10-300 mg,10-200 mg, 10-100 mg, or 10-50 mg of memantine (e.g., 10 mg, 11.25 mg,12.5 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 33.75 mg, 37.5 mg, 40 mg,45 mg, 50 mg, 60 mg, 65 mg, 67.5 mg, 70 mg, 75 mg, 80 mg, 120 mg, 180mg, 240 mg or 300 mg).

In one embodiment, a composition is prepared using the methods describedherein, wherein such composition comprises memantine or amantadine and arelease modifying excipient. The excipient is present in an amountsufficient to ameliorate or reduce acute toxicity associated with thememantine or amantadine relative to an immediate release (IR)formulation of memantine (e.g., Namenda) or amantadine (e.g.,Symmetrel). The use of such composition increases the safety in theadministration of such agents, enabling reduced dosing frequency withsimilar or higher doses of the NMDAr antagonist as compared with thepresently available forms of these pharmaceutical products.

Reduced Time to Therapeutic Concentration and Efficacy

Immediate release (IR) formulations of memantine (e.g., Namenda) aretypically administered at low doses (e.g., 5 mg/day) and progressivelyadministered at increasing frequency and dose over time to reach asteady state serum concentration that is therapeutically effective.According to the manufacturer's FDA approved label, Namenda, animmediate release (IR) formulation of memantine, is first administeredto subjects at a dose of 5 mg per day. After a period of timeone weekacclimation period, subjects are administered with this dose twicedaily. Subjects are next administered with a 5 mg and 10 mg dosing perday and finally administered with 10 mg Namenda twice daily. FIG. 2Dshows the average serum concentration each day as predicted by thepharmacokinetic software, GastroPlus, from Simulations Plus. Using thisdosing regimen, a therapeutically effective steady state serumconcentration may be achieved within 30 days of the onset of therapy.Using a modified release formulation comprising (22.5 mg memantine)however, a therapeutically effective steady state concentration may beachieved substantially sooner, without using a dose escalating regimen.As shown in FIG. 2D, such concentration is predicted to be achievedwithin thirteen days of the onset of therapy. Furthermore, the slopeduring each absorption period for the sustained release formulation isless (i.e. not as steep) as the slope for Namenda. Accordingly, thedC/dT of the sustained release formulation is reduced relative to theimmediate release formulation even though the dose administered islarger than for the immediate release formulation. Based on this model,a sustained release formulation of memantine may be administered to asubject in an amount that is approximately the full strength dose (orthat effectively reaches a therapeutically effective dose) from theonset of therapy and throughout the duration of treatment. Accordingly,a dose escalation would not be required.

Thus in one embodiment, a composition is prepared using the methodsdescribed herein, wherein such composition comprises a therapeuticallyeffective amount of memantine or amantadine and an excipient foradministration to a subject without prior administration of asubtherapeutic amount of same active agent (i.e. memantine oramantadine) to the same subject. Specifically, for an indication such asAlzheimer's disease, where a therapeutically effective amount ofmemantine is typically 20 mg per day, the administration of memantine tothe subject is initiated at 22.5 mg per day or more, instead of asubtherapeutic amount (e.g., 5 mg per day as currently indicated in themanufacturer's FDA-approved label for Namenda).

Treatment of a subject with the subject of the present invention may bemonitored using methods known in the art. The efficacy of treatmentusing the composition is preferably evaluated by examining the subject'ssymptoms in a quantitative way, e.g., by noting a decrease in thefrequency or severity of symptoms or damaging effects of the condition,or an increase in the time for sustained worsening of symptoms. In asuccessful treatment, the subject's status will have improved (i.e.,frequency or severity of symptoms or damaging effects will havedecreased, or the time to sustained progression will have increased). Inthe model described in the previous paragraph, the steady state (andeffective) concentration of the NMDAr antagonist is reached in 25% 40%50% 60% 70% 75% 80% less time than the dose escalated approach.

In another embodiment, a composition is prepared using the methodsdescribed herein, wherein such composition comprises memantine oramantadine and a release modifying excipient, wherein the excipient ispresent in an amount sufficient to ameliorate or reduce thedose-dependent toxicity associated with the memantine or amantadinerelative to an immediate release (IR) formulation of memantine, such asNamenda, or amantadine, such as Symmetrel. The use of these compositionsenables safer administration of these agents, and even permits the safeuse of higher levels for appropriate indications, beyond the usefulrange for the presently available versions of memantine (5 mg and 10 mgper dose to 20 mg per day) and amantadine (100 mg to 300 mg per day withescalation).

Indications Suitable for Treatment

Conditions suitable for treatment according to this invention includeseizure disorders, pain syndromes, neurodegenerative diseases (includingmotor neuron diseases, myelopathies, radiculopathies, and disorders ofthe sympathetic nervous system), dementias, cerebrovascular conditions,movement disorders, brain trauma, cranial nerve disorders,neuropsychiatric disorders, and other disease neuropathies (includingviral associated neuropathies, diabetes associated neuropathies,Guillian-Barre syndrome, dysproteinemias, transthyretin-inducedneuropathies, and carpal tunnel syndrome).

As used herein, seizure disorders include complex partial seizures,simple partial seizures, partial seizures with secondary generalization,generalized seizures (including absence, grand mal (tonic clonic),status epilepticus, tonic, atonic, myoclonic), neonatal and infantilespasms, drug-induced seizures, trauma-induced seizures, and febrileseizures, and additional specific epilepsy syndromes such as juvenilemyoclonic epilepsy, Lennox-Gastaut, mesial temporal lobe epilepsy,nocturnal frontal lobe epilepsy, progressive epilepsy with mentalretardation, and progressive myoclonic epilepsy, as well as seizuresassociated with CNS mass lesions.

Pain syndromes include, for example, headaches (e.g., migraine, tension,and cluster), acute pain, chronic pain, neuropathic pain, nociceptivepain, central pain and inflammatory pain, drug-induced neuropathic pain,causalgia, complex regional pain syndrome types I and II, and reflexsympathetic dystrophy (RSDS).

Neurodegenerative diseases include Alzheimer's disease, Parkinson'sDisease, multiple sclerosis, Huntington's Disease, ALS, spinal muscularatrophy, muscular dystrophies prion-related diseases, cerebellar ataxia,Friedrich's ataxia, SCA, Wilson's disease, RP, Gullian Barre syndrome,Adrenoleukodystrophy, Menke's Sx, cerebral autosomal dominantarteriopathy with subcortical infarcts (CADASIL), Charcot Marie Toothdiseases, neurofibromatosis, von-Hippel Lindau, Fragile X, spasticparaplegia, tuberous sclerosis complex, Wardenburg syndrome, spinalmotor atrophies, Tay-Sach's, Sandoff disease, familial spasticparaplegia, myelopathies, radiculopathies, encephalopathies associatedwith trauma, radiation, drugs and infection, and disorders of thesympathetic nervous system (e.g., Shy Drager (familial dysautonomia),diabetic neuropathy, drug-induced and alcoholic neuropathy).

Dementias include Alzheimer's disease, Parkinson's disease, Pick'sdisease, fronto-temporal dementia, vascular dementia, normal pressurehydrocephalus, Huntington's disease, and MCI.

Cerebrovascular conditions amenable to treatment according to thepresent invention include Cerebrovascular disease and strokes (e.g,thrombotic, embolic, thromboembolic, hemorrhagic (including AVM andberry aneurysms), venoconstrictive, and venous).

Included in movement disorders are Parkinson's disease, dystonias,benign essential tremor, tardive dystonia, tardive dyskinesia, andTourette's syndrome.

Brain trauma as used herein includes traumatic brain and spinal cordinjuries as well as brain injuries from radiation.

Cranial nerve disorders include trigeminal neuropathy, trigeminalneuralgia, Menier's syndrome, glossopharangela neuralgia, dysphagia,dysphonia, cranial nerve palsies and Bell's palsy.

Neuropsychiatric disorders include panic syndrome, general anxietydisorder, phobic syndromes of all types, mania, manic depressiveillness, hypomania, unipolar depression, depression, stress disorders,PTSD, somatoform disorders, personality disorders, psychosis, andschizophrenia), and drug dependence/addiction (e.g., alcohol,psychostimulants (eg, crack, cocaine, speed, meth), opioids, andnicotine), and drug-induced psychiatric disorders.

Other disease neuropathies that may be treated with the compositions andmethods described herein include Guillian-Barre, diabetes associatedneuropathies, dysproteinemias, transthyretin-induced neuropathies,neuropathy associated with HIV, herpes viruses (including herpes zoster)or other viral infection, neuropathy associated with Lyme disease,carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-inducedneuropathies, leprous neuropathy, Bell's palsy, compressionneuropathies, sarcoidosis-induced neuropathy, polyneuritis cranialis,heavy metal induced neuropathy, transition metal-induced neuropathy,drug-induced neuropathy, post-meningitis syndrome, post-polio syndrome,prion diseases, and radiation associated neuropathic syndromes.

Other diseases amenable to treatment with the present invention includefatigue syndromes (e.g., chronic fatigue syndrome and fibromyalgia),ataxic syndromes, olivopontoicerebellar degeneration, striatonigraldegeneration, and axonic brain damage.

Because the NMDAr antagonist in the present compositions reaches atherapeutically effective steady state in a shorter period of time thanimmediate release formulations (e.g., within the course of the firstfive, seven, nine, ten, twelve, fifteen, or twenty days ofadministration), the present invention is particularly useful for thetreatment of neuropsychiatric disorders such as depression, agitation,anxiety, seizure disorders such as grand mal seizures, statusepilepticus, migraine pain treatment and prophylaxis, Alzheimer'sdisease, Parkinson's disease, and traumatic brain and spinal cordinjury.

Also, the higher doses enabled by the present invention are expected tobe of particular importance for dementias including Alzheimer's disease,Parkinson's disease, and vascular dementia, pain syndromes, includingheadaches and migraines, seizure disorders, movement disorders, andbrain trauma.

Furthermore, the ease of use and convenience of a dosage form provideddeveloped to be delivered at once per day or less frequentadministration at a therapeutically effective quantity from the onset oftherapy is of value in treatment of dementias including Alzheimer'sdisease and Parkinson's disease, seizure disorders, pain syndromes, andcerebrovascular conditions.

Formulations for Alternate Specific Routes of Administration

The pharmaceutical compositions may be optimized for particular types ofdelivery. For example, pharmaceutical compositions for oral delivery areformulated using pharmaceutically acceptable carriers that are wellknown in the art. The carriers enable the agents in the composition tobe formulated, for example, as a tablet, pill, capsule, solution,suspension, sustained release formulation; powder, liquid or gel fororal ingestion by the subject.

The NMDAr antagonist may also be delivered in an aerosol spraypreparation from a pressurized pack, a nebulizer or from a dry powderinhaler. Suitable propellants that can be used in a nebulizer include,for example, dichlorodifluoro-methane, trichlorofluoromethane,dichlorotetrafluoroethane and carbon dioxide. The dosage can bedetermined by providing a valve to deliver a regulated amount of thecompound in the case of a pressurized aerosol.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral,intranasal or respiratory route for local or systemic effect.Compositions in preferably sterile pharmaceutically acceptable solventsmay be nebulized by use of inert gases. Nebulized solutions may bebreathed directly from the nebulizing device or the nebulizing devicemay be attached to a face mask, tent or intermittent positive pressurebreathing machine. Solution, suspension or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

In some embodiments, for example, the composition may be deliveredintranasally to the cribriform plate rather than by inhalation to enabletransfer of the active agents through the olfactory passages into theCNS and reducing the systemic administration. Devices commonly used forthis route of administration are included in U.S. Pat. No. 6,715,485.Compositions delivered via this route may enable increased CNS dosing orreduced total body burden reducing systemic toxicity risks associatedwith certain drugs.

Additional formulations suitable for other modes of administrationinclude rectal capsules or suppositories. For suppositories, traditionalbinders and carriers may include, for example, polyalkylene glycols ortriglycerides; such suppositories may be formed from mixtures containingthe active ingredient in the range of 0.5% to 10%, preferably 1%-2%.

The composition may optionally be formulated for delivery in a vesselthat provides for continuous long-term delivery, e.g., for delivery upto 30 days, 60 days, 90 days, 180 days, or one year. For example thevessel can be provided in a biocompatible material such as titanium.Long-term delivery formulations are particularly useful in subjects withchronic conditions, for assuring improved patient compliance, and forenhancing the stability of the compositions.

Optionally, the NMDA receptor antagonist is prepared using the OROS®technology, described for example, in U.S. Pat. Nos. 6,919,373,6,923,800, 6,929,803, 6,939,556, and 6,930,128, all of which are herebyincorporated by reference. This technology employs osmosis to provideprecise, controlled drug delivery for up to 24 hours and can be usedwith a range of compounds, including poorly soluble or highly solubledrugs. OROS® technology can be used to deliver high drug doses meetinghigh drug loading requirements. By targeting specific areas of thegastrointestinal tract, OROS® technology may provide more efficient drugabsorption and enhanced bioavailability. The osmotic driving force ofOROS® and protection of the drug until the time of release eliminate thevariability of drug absorption and metabolism often caused by gastric pHand motility.

Formulations for continuous long-term delivery are provided in, e.g.,U.S. Pat. Nos. 6,797,283; 6,764,697; 6,635,268, and 6,648,083.

If desired, the components may be provided in a kit. The kit canadditionally include instructions for using the kit.

Additional Methods for Making Modified Release Formulations

Additional methods for making modified release formulations aredescribed in, e.g., U.S. Pat. Nos. 5,422,123, 5,601,845, 5,912,013, and6,194,000, all of which are hereby incorporated by reference.

Alternatively, the compositions of the present invention may beadministered transdermally. Preparation for delivery in a transdermalpatch can be performed using methods also known in the art, includingthose described generally in, e.g., U.S. Pat. Nos. 5,186,938 and6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89/09051,incorporated herein by reference in their entireties. A patch is aparticularly useful embodiment with drugs having absorption problems.Patches can be made to control the release of skin-permeable activeingredients over a 12 hour, 24 hour, 3 day, and 7 day period. In oneexample, a 2-fold daily excess of an NMDAr antagonist is placed in anon-volatile fluid. Given the amount of the agents employed herein, apreferred release will be from 12 to 72 hours.

Transdermal preparations of this form will contain from 1% to 50% activeingredients. The compositions of the invention are provided in the formof a viscous, non-volatile liquid. Preferably, the NMDAr antagonist willhave a skin penetration rate of at least 10-9 mole/cm2/hour. At least 5%of the active material will flux through the skin within a 24 hourperiod. The penetration through skin of specific formulations may bemeasures by standard methods in the art (for example, Franz et al., J.Invest. Derm. 64:194-195 (1975)). Providing the NMDAr antagonist in theform of patches is useful given that these agents have relatively highskin fluxes.

In some embodiments, for example, the composition may be delivered viaintranasal, buccal, or sublingual routes to the brain rather than byinhalation to enable transfer of the active agents through the olfactorypassages into the CNS and reducing the systemic administration. Devicescommonly used for this route of administration are included in U.S. Pat.No. 6,715,485. Compositions delivered via this route may enableincreased CNS dosing or reduced total body burden reducing systemictoxicity risks associated with certain drugs.

Preparation of a Pharmaceutical Composition for Delivery in aSubdermally Implantable device can be performed using methods known inthe art, such as those described in, e.g., U.S. Pat. Nos. 3,992,518;5,660,848; and 5,756,115.

Using the formulations and methods described herein, we have producednumerous formulations of NMDAr antagonists (e.g., memantine andamantadine) having modified release profiles (more than 50). Exemplaryformulations are provided in the Examples.

The invention will be illustrated in the following non-limitingexamples.

EXAMPLES Example 1 Measuring Release Profiles for Aminoadamantanes InVitro

Compositions containing an aminoadamantane were analyzed for release ofthe aminoadamantane, according to the USP type II apparatus at a speedof 50 rpm. The dissolution media used were water, 0.1N HCl, or 0.1N HCladjusted to pH 6.8 at 2 hours with phosphate buffer. The dissolutionmedium was equilibrated to 37±0.5° C.

The USP reference assay method for amantadine was used to measure thefraction of memantine released from the compositions prepared herein.Briefly, 0.6 mL sample (from the dissolution apparatus at a given timepoint) was placed into a 15 mL culture tube. 1.6 mL 0.1% BromocresolPurple (in acetic acid) was added and vortexed for five seconds. Themixture was allowed to stand for approximately five minutes. 3 mLChloroform was added and vortexed for five seconds. The solution wasnext centrifuged (speed 50 rpm) for five minutes. The top layer wasremoved with a disposable pipette. A sample was drawn into 1 cm flowcell and the absorbance was measured at 408 nm at 37° C. and comparedagainst a standard curve prepared with known quantities of the sameaminoadamantane. The quantity of determined was plotted against thedissolution time for the sample.

Example 2 Preparation of Memantine-Containing Cores to be Coated with anEnteric Coating

Memantine-containing cores are prepared as follows and as described, forexample, in U.S. Pat. No. 4,606,909. Cores (containing 24% talc) areprepared using 0.97 kg memantine, 0.2 kg sodium laurylsulphate, 0.5 kgmicrocrystalline cellulose, 5.93 kg saccharose powder, and 2.4 kg talc.Memantine and sodium laurylsulphate are co-comminuted by passage througha grinder using a 0.5 mm sieve. The ground mixture is mixed withmicrocrystalline cellulose, saccharose, and talc in a planet mixer. 10kg of the resulting mixture is moistened with 0.8 kg purified water andmixed in a planet mixer until the mixture is slightly lumpy. The moistmixture is extruded through a 0.5 mm sieve. The first kilograms ofextrudate passing the sieve is powdery and re-extruded. The resultingextrudates form strings, breaking off in lengths of 10-30 cm. 2 kg ofthe extruded strings is formed into compact-shaped cores in aMarumerizer™ and the resulting compact-shaped cores are dried in afluidized bed dryer and sieved through a separator (the upper sieve(0.71 mm) and the bottom sieve (0.46 mm). Using the same technique,cores (containing 10% talc) are prepared using 0.97 kg memantine, 0.2 kgsodium laurylsulphate, 1.0 kg microcrystalline cellulose, 6.83 kgsaccharose powder, and 1.0 kg talc.

The release of memantine is measured, at a pH 7.5 for the corescontaining 24% talc and 10% talc, respectively. The reduction in thetalc content from 24% to 10% decreases the release weight of memantinefrom the core.

An enteric coating suspension, which further delays the release ofmemantine, is prepared by homogenizing 9.0 kg Eudragit™ S 12.5 togetherwith 0.135 kg acetyltributylcitrate, 0.9 kg talc, and 7.965 kgisopropanol. 10 kg of the above-described cores containing 10% talc arecoated with 4.167 kg of this coating suspension in a fluidized bed andthe resulting pellets are covered with talcum. For the preparation of apharmaceutical dosage form, 1000 of these pellets are filled in acapsule No. 1, such that each of the capsule contains 25 mg memantine.

Example 3 Preparation of Amantadine Extended Release Capsules

Amantadine extended release capsules may be formulated as follows or asdescribed, for example, in U.S. Pat. No. 5,395,626.

A. Composition: Unit Dose

The theoretical quantitative composition (per unit dose) for amantadineextended release capsules is provided below.

Component % weight/weight mg/Capsule Amantadine 68.34 200.00  OPADRY ®Clear YS-3-7011 ¹ 1.14  5.01 (Colorcon, Westpoint, PA) Purified Water,USP ² — — Sugar Spheres, NF 12.50 54.87 OPADRY ® Clear YS-1-7006 ³ 4.4819.66 (Colorcon, Westpoint, PA) SURELEASE ® E-7-7050 ⁴ 13.54 59.44(Colorcon, Westpoint, PA) Capsules ⁵ — — TOTAL 100.00%     338.98 mg ⁶ ¹A mixture of hydroxypropyl methylcellulose, polyethylene glycol,propylene glycol. ² Purified Water, USP is evaporated during processing.³ A mixture of hydroxypropyl methylcellulose and polyethylene glycol ⁴Solid content only of a 25% aqueous dispersion of a mixture of ethylcellulose, dibutyl sebacate, oleic acid, ammoniated water and fumedsilica. The water in the dispersion is evaporated during processing. ⁵White, opaque, hard gelatin capsule, size 00. ⁶ Each batch is assayedprior to filling and the capsule weight is adjusted as required toattain 200 mg amantadine per capsule.

The quantitative batch composition for amantadine extended releasecapsule is shown below. (Theoretical batch quantity 25,741 capsules):

Step 1: Prep of Amantadine HCl Beads (bead Build-up #1) Component Weight(kg) Amantadine 12.000  OPADRY ® Clear YS-3-7011 0.200 Purified Water,USP 5.454 Sugar Sphere, NF 4.000 Total Weight Amantadine Beads  16.200kg

The amantadine beads obtained from step 1 are used as follows.

Step 2: Clear & Sustained Release Bead Coating #1 Component Weight (kg)Amantadine Beads 8.000 OPADRY ® Clear YS-1-7006 0.360 Purified Water,USP 5.928 Surelease ® E-7-7050 0.672 Total Weight Clear Coated 9.032 kgSustained Release Beads

The sustained release beads obtained from step 2 are used as follows.

Step 3: Amantadine HCl Beads (Build-up #2) Component Weight (kg)Sustained Release Beads 8.000 Amantadine 4.320 OPADRY ® Clear YS-3-70110.072 Purified Water, USP 1.964 Total Weight Amantadine Beads 12.392 kg

The amantadine beads obtained from step 3 are formulated as follows.

Step 4: Clear & Sustained Release Bead Coating #2 Component Weight (kg)Amantadine Beads 10.000 OPADRY ® Clear YS-1-7006 0.250 Purified Water,USP 6.450 Surelease ® E-7-7050 1.050 Total Weight Amantadine 11.300 kgExtended Release Beads

Step 5: Capsule Filling—Gelatin capsules, size 00, are filled with 339mg of the amantadine beads prepared in step 4.

Examples 4-11 Extended Release Formulation of Rimantidine

The NMDAr antagonist, rimantidine, is formulated for extended release asfollows (see, for example, U.S. Pat. No. 5,912,013).

Example 4 Core Pellets

Weight Percent Kilograms MCC 25.0 0.25 Hydroxypropylmethylcellulose 10.00.10 Phthalate (HPMCP) Tartaric Acid 10.0 0.10 Sodium Monoglycerate 7.50.075 DSS 0.5 0.005 Rimantadine 47.0 0.47 TOTAL 100.0% 1.00 kg CoatingCellulose Acetate Phthalate (CAP) 60.0 0.60 Ethylcellulose 25.0 0.25PEG-400 15.0 0.15 TOTAL 100.0% 1.00 kg

Example 5 Coating for Core Pellets from Example 4

Weight Percent Kilograms Ethacrylic/Methacrylic Acid 85.0 0.85 Esters(Eudragit line of enteric polymers) Propylene Glycol 14.0 0.14 Talc 1.00.01 TOTAL 100.0% 1.00 kg

Example 6 Coating for Core Pellets from Example 4

Weight Percent Kilograms CAP 65.0 0.65 HPMCP 15.0 0.15 PEG-400 10.0 0.10PEG-8000 10.0 0.10 TOTAL 100.0% 1.00 kg

Example 7 Core Pellet

Weight Percent Kilograms MCC 25.0 0.25 Mono/Di/Tri-glyceride Mixture15.0 0.15 Tartaric Acid 10.0 0.10 CAP 10.0 0.10 DSS 0.8 0.008Rimantadine 39.2 0.392 TOTAL 100.0% 1.00 kg Coating as in Example 4

Example 8 Core Pellet as in Example 8, Coating as in Example 5 Example 9Core Pellet as in Example 8, Coating as in Example 6 Example 10 Coatingfor Core Pellet as in Example 9

Weight Percent Kilograms Shellac 85.0 0.85 Mineral Oil 13.0 0.13 SLS 0.50.005 Talc 1.5 0.015 TOTAL 100.0% 1.00 kg

Example 11 Core Pellet as in Example 4, Coating as in Example 10 Example12 Preparation of Memantine Controlled Release

Different sustained release tablet formulations of memantine weredeveloped, each of which is associated with a characteristic in vitrodissolution profile. As described in further detail below, the sustainedrelease formulations reach a superior pharmacokinetic profiletherapeutically. The sustained release profile was achieved using asustained release matrix or a sustained release coated tablet. Thephysical characteristics of the active, a description of the formulationcomposition, an outline of the small scale production process, and thevalidated analytical methods are presented below.

Drug Substance Information

API Name Memantine Molecular Weight 215.8 for HCl salt, 178.3 for freebase Melting Point ° C. 258-295° C. pK_(a) 10.27 Aqueous Solubility40-45 mg/ml at pH 2-9 Stability T_(1/2) > 24 hours in aqueous buffer, pH4.0-7.4 and rat plasma

Formulation Composition Formulation # 1 Formulation # 2 Type of TabletSustained release Sustained release matrix coated tablet Memantine HCL13.5% 15.25%    (22.5 mg) Avicel PH102 60.0% 69.0%   Eudragit RS-30D15.4% 14.8%   (aqueous dispersion) HPMC K100M 10.1% — Magnesium Stearate 1.0% 1.0%  Coating: — Additional 6% coat      70% Eudragit RL-30D 21% (aqueous dispersion) 30% Eudragit RS-30D 9% (aqueous dispersion) Talc 9%TEC 2% H₂O 59%  Total Tablet Weight 150 mg 159 mg Formulation #1:Memantine formulated with a sustained release matrix

Formulation #1 was produced as follows. Memantine was formulated asshown in the table below.

Component mg/tablet Core Tablets - 22.5 mg - % Comp. Solid TotalFormulation 1292-22.5-10A Solid weight weight weight (g) Granulationfrom 1292-12 - 150 grams Memantine HCl 13.51 22.5 22.79 Avicel ® PH10260.04 100.0 101.28 Eudragit RS-30D (30% w/v 15.37 25.6 25.92 aqueousdispersion) Extragranular Excipient HPMC K100M 10.08 16.8 17.00Magnesium Stearate 1.01 1.6 1.7 Total 100.0 166.5 168.7 (solid weight)

API is bag blended with Avicel PH102 and sieved through an 18-meshscreen. The mix is next dried in a low shear mixer. The blend is wetmassed with Eudragit and the granulation is dried in an oven at 40-45°C. for 12 hours. The granulation is next pass dried through anAlexanderwerk Mill set up with 0.8 mm screen, producing the intermediateactive blend. HPMC was sieved through a 30 mesh screen. The screenedHPMC was premixed with an equal amount of the intermediate active blend,referred to herein as 1292-12 and bag blended for two minutes. The blendwas next lubricated with Magnesium Stearate in a low shear blender. Asample from this blend was collected for LOD (Loss on Drying) testing onComputrac MAx 2000 set at 105° C. The final blend is then compressed andtables are punched using a D3B set up with 0.25 inch standard roundconcave punch tooling. The dissolution profile of this formulation isprovided in FIG. 6 (% Label claim vs. time).

Formulation 2: Memantine Formulated Using A Sustained Release CoatedMatrix Component % Comp. mg/tablet Total Core Tablets - 22.5 mg - Solidweight Solid weight weight (g) Memantine HCl active 15.25 22.5 93.80Avicel ® PH102 68.96 101.75 424.20 Eudragit RS-30D (30% w/v 14.79 21.83303.3* aqueous dispersion) Extragranular Excipient HPMC K100M 10.08 16.817.00 Magnesium Stearate 1.01 1.6 1.7 Total 100.0 166.5 168.7 (solidweight) *303.3 g of Eudragit RS-30D aqueous dispersion contains 91 g ofsolid polymer and 212.3 g of liquid.

Memantine HCl is first bag blended with Avicel PH102 for one minute. Thedry blend is sieved through an 18 mesh screen into a poly bag and bagblended for one minute. The mixture is loaded into a low-shear mixer anddried for two minutes. The blend was wet massed with Eudragit and thegranulation was next dried in an oven at 40-45° C. for 12 hours. Thedried granulation is next passed through an Alexanderwerk Mill set upwith a 0.8 mm screen. Sieved magnesium stearate (30-mesh) was next addedto the milled mix and bag blended. The final blend was next compressedand tablets were punched using a D3B 0.25 inch standard round punch.

The coat tablet was prepared as follows. To prepare the coat, EudragitRL-30D & Eudragit RS-30D was added to bubble free purified water whilevortexing. TEC is next added and mixed for >30 minutes. Talc is slowlyadded and mixed to obtain homogenous dispersion. The coating desertionwas next screened through 60-mesh sieve. The coating parameters are asfollows (O'Hara Lab II-X 15″pna): inlet temp: 37-40° C.; outlet temp:25-28° C.; air flow rate: 150-175 CFM; pan speed: 8-9 rpm; and spraydistance: 6-8″.

Tablets were next coated. The exhaust temperature and coating speed(weight change/minute) were first calibrated and tables were coated fora set amount of time. Tablets were allowed to roll for 3 minutes at aconstant temperature (37-40° C.) and tablets were next cooled andtransferred to a forced air oven (40° C.) for 24 hours to dry.

Example 13 Film-Coated Formulation

Film-coated tablets were formulated by coating a memantine tablet withor without an Opadry® subcoat and with a Surelease® overcoat. 2% Opadry®based coating with 2% Surelease® overcoat presented a desired releaseprofile.

Example 14 Matrix Core Tablet

Matrix Core tablets were formulated as shown in the table below.(Appearance=good, weight=167 mg; hardness=5.1 kg; friability 100 revs:0.6%). Low coating weight gain was associated with rapid hydration ofcoating, whereas high coating weight gain was associated with slowhydration of coating.

% w/w mG/Tablet Granulation Memantine HCL 14 22.5 Avicel PH102 60 100.0Eudragit RS-30D 15 25.6 Extragranular Methocel K100M* 10 16.8 MgStearate 1 1.6 Total 100 166.5

Coated beads or granules were compressed into a tablet. A honeycomb-likestructure is established during compression. The tablet disintegratesinto beads and granules, whose individual properties then controlrelease of memantine. A HPMC subcoat may optionally be used. Waterpenetrates the Surelease coating, which remains intact thereforetrapping the HPMC subcoat between the core and the external coating. Thewater-soluble HPMC subcoating hydrates. While it is water soluble it isa large molecular weight polymer which cannot diffuse out through thewater insoluble ethycellulose coating. Release of drug will not occuruntil water reaches the core. The delay should therefore vary as afunction of the amount of HMPC in the tablet. Water reaches the outsidesurface of the core and memantine dissolves. High water solubilityestablishes a high concentration gradient. Dissolved memantine nextdiffuses through the hydrated HPMC layer and the porous ethylcellulosecoating. Accordingly, a high level of ethylcellulose coating controlsthe release rate by the external coating whereas a lower level ofethylcellulose coating results in erosion, sloughing off of the hydratedHPMC, and the control of release being governed by the matrix bead.

Example 15 In Vitro Dissolution Profile of Sustained ReleaseFormulations of Memantine

Various sustained release formulations of memantine were prepared asfollows.

Matrix Tablet Formulation 5001-6601 Memantine HCL (22.5 mg) 13.51%Avicel PH102 60.04% Eudragit RS-30D (30% w/w aqueous dispersion) 15.37%HPMC K100M 10.08% Magnesium Stearate 1.00% Total Component Weight 166.5mg

Coated Tablet Formulation 5001-6701 Memantine HCL (22.5 mg) 13.21%Avicel PH102 58.72% Eudragit RS-30D (30% w/w aqueous dispersion) 15.03%HPMC K100M 9.86% Magnesium Stearate 0.98% Surelease ® Clear,(Formulation E-7-19010, 2.20% Colorcon) Total Component Weight 170.2 mg

Coated Tablet Formulation 5001-680 Memantine HCL (22.5 mg) 12.73% Avicel PH102 56.55%  Eudragit RS-30D (30% w/w aqueous dispersion)14.48%  HPMC K100M 9.50% Magnesium Stearate 0.94% Opadry ® Clear,(Formulation YS-1-7006, Colorcon) 3.00% Surelease ® Clear, (FormulationE-7-19010, 2.80% Colorcon) Total Component Weight 176.2 mg

Coated Tablet Formulation 5001-6804 Memantine HCL (22.5 mg) 12.64% Avicel PH102 55.98%  Eudragit RS-30D (30% w/w aqueous dispersion)14.33%  HPMC K100M 9.40% Magnesium Stearate 0.93% Opadry ® Clear,(Formulation YS-1-7006, Colorcon) 3.00% Surelease ® Clear, (FormulationE-7-19010, 3.80% Colorcon) Total Component Weight 178 mg

Coated Bead Formulation 5001-6990 20% Memantine HCL (22.5 mg) & 75%Eudragit RS-30D (30% w/w aqueous dispersion) Opadry ® Clear,(Formulation YS-1-7006, Colorcon) 2.00%  Surelease ® Clear, (FormulationE-7-19010, 10% Colorcon) Total Component Weight NA

Coated Bead Formulation 5001-6991 20% Memantine HCL (22.5 mg) & 65%Eudragit RS-30D (30% w/w aqueous dispersion) Opadry ® Clear,(Formulation YS-1-7006, Colorcon) 10.00%   Eudragit RS-30D coat(30% w/waqueous dispersion) 25% Total Component Weight NA

Coated Bead Formulation 5001-6992 20% Memantine HCL (22.5 mg) & 55%Eudragit RS-30D (30% w/w aqueous dispersion) Opadry ® Clear,(Formulation YS-1-7006, Colorcon) 10.00%   Eudragit RS-30D coat(30% w/waqueous dispersion) 35% Total Component Weight NA

Coated Bead Formulation 5001-6993 20% Memantine HCL (22.5 mg) & 53%Eudragit RS-30D (30% w/w aqueous dispersion) Opadry ® Clear,(Formulation YS-1-7006, Colorcon) 30.00%   Surelease ® Clear,(Formulation E-7-19010, 17% Colorcon) Total Component Weight NA

Exemplary in vitro dissolution profiles of sustained releaseformulations of memantine and Namenda are shown in FIGS. 2A-2C and3A-3B. The dissolution profiles of the sustained release memantineformulations in neutral medium (FIG. 2A) are substantially identical totheir dissolution profiles in an acidic dissolution medium (FIG. 2B).

FIG. 2C is a graph showing effect of medium on the release profile ofmemantine from matrix tablets. Testing was performed using the R&Dmethod using Apparatus 2 at 50 RPM. Three media were employed: Vessels1&2=Water; Vessels 3&4=pH 1.2 Buffer; Vessels 5&6=pH 1.2 Buffer for 2hours, then pH adjusted to 6.8. There were no significant differences inthe profiles for the first two hours or between the profile obtained ina pH 1.2 buffer and water. The switch to a buffer having a pH 6.8,however, slowed down release. Accordingly, optimal media testing may bewater (pH of a solution containing approximately 22.5 mg Memantine HClin water is 7.7, consistent with a dilute solution of a base that has apKa of about 9-10).

Formulation of Memantine HCl SR Capsules as Coated Pellets (22.5 Mg)

Memantine was formulated as shown in the table below.

Qty/unit Ingredients (mg) Memantine Hydrochloride 22.5 HPMC 5 cps 9.5Non-pareils (Celpheres) 90.0 Isopropyl alcohol q.s. Dichloromethane q.sTotal 122.0

The memantine pellets were next coated using a Wurster coater. TheEthylcellulose: HPMC ratios of coating formulation I and coatingformulation II were 9:1 and 8:2, respectively (see table below).

% Ingredients Coating Formula I Coating Formula II Ethylcellulose 7 cps8.10 6.46 HPMC 5 cps 0.92 1.61 Miglyol 812 N 0.42 0.32 Isopropyl alcohol72.54 67.31 Dichloromethane 18.02 24.30 Coating levels (%) 8.7, 11.2,13.0 & 16.5 8.0, 11.6, 14.4 & 16.11

Once coated, the memantine pellets were encapsulated by hand filling,such. Each capsule contained 22.5 mg of memantine. The capsule size was‘3.’

The dissolution profiles of the above formulations were next determinedwith a USP II (Paddle) system, using water (500 mL) as a dissolutionmedium at 50 rpm. Different coating levels (% w/w) were employed. Therelease profile of each memantine capsule (22.5 mg) was determined at 1,2, 4, 6, 8, and 12 hours (see tables below).

Release Data of Memantine HCl SR Capsules 22.5 mg filled with pelletscoated with Coating formula I at different coating levels (% w/w) Time(hours) 8.70% 11.20% 13% 16.50% 0 0 0 0 0 1 11 8 6 4 2 34 23 18 11 4 6951 41 28 6 82 68 57 42 8 88 76 67 54 12 95 86 80 68

Release Data of Memantine HCl SR Capsules 22.5 mg filled with pelletscoated with Coating formula II at different coating levels (% w/w) Time(Hours) 8% 11.60% 14.40% 16.60% 0 0 0 0 0 1 30 14 11 5 2 65 39 31 17 493 69 63 40 6 99 83 76 57 8 100 90 86 65 12 100 99 95 83

Drug release was sustained up to 12 hours, in a non-linear fashion. Inmost cases, pellets showed faster release after 2 hours. To linearisethe release profile up to 12 hours with around 100% drug release, druglayering and coating compositions may be varied.

Example 16 Predicted Plasma Profile of Memantine Sustained Release

Using the formulations and dissolution profiles described in Example 14,the serum concentrations resulting from single or multipleadministrations of memantine were calculated using the pharmacokineticsoftware, GastroPlus, from Simulations Plus (see FIG. 2D). Theadministration of either of the sustained release formulations achievesa therapeutically effective steady state serum concentration much soonerthan with Namenda (13 days versus 30 days from the start of treatmenttherapy). Furthermore, the initial slope of the sustained releaseformulation is less than the slope obtained with the immediate releaseformulation.

Example 17 Patch Providing Extended Release of Memantine

As described above, extended release formulations of an NMDA antagonistmay be formulated for topical administration. Memantine transdermalpatch formulations may be prepared as described, for example, in U.S.Pat. Nos. 6,770,295 and 6,746,689, hereby incorporated by reference.

For the preparation of a drug-in-adhesive acrylate, 5 g of memantine isdissolved in 11 g of ethanol and is added to 20 g of Durotak 387-2287(National Starch & Chemical, U.S.A.). The drug gel is coated onto abacking membrane (Scotchpak 1012; 3M Corp., U.S.A.) using a coatingequipment (e.g., RK Print Coat Instr. Ltd, Type KCC 202 control coater).The wet layer thickness is 400 μm. The laminate is dried for 20 minutesat room temperature and then for 30 minutes at 40° C. A polyesterrelease liner is laminated onto the dried drug gel. The sheet is cutinto patches and stored at 2-8° C. until use (packed in pouches). Theconcentration of memantine in the patches ranges between 5.6 and 8mg/cm².

Example 18 Patch Providing Extended Release of Memantine

A patch allowing the extended release of memantine may be prepared asfollows. The matrix patch is composed of 1 mm thick polyolefin foam (asan occlusive backing) coated with an acrylate matrix that includes amixture of memantine and an intradermal-penetration agent in an acrylatepolymer. The matrix is prepared by mixing memantine (20 weight percent);acrylate polymer (Durotak® 387-2052, 75 weight percent);intradermal-penetration agent; aluminumacetylacetonate (Al(ACAC)₃, 0.4weight percent, as a crosslinker); and ethanol until homogeneous. Thehomogeneous mixture is then coated on polyolefin foil with a hand-coatermachine to an average thickness of about 270 μm. The coated foil isdried for about one hour at about 50° C. to evaporate the ethanol. Theresulting patch weighs approximately 50 g/m² dry.

Example 19 Determination of Increased-Dose Tolerability for Memantine SRformulations

A study to determine safety and tolerability of increased dosing forMemantine SR is described below. The study results are expectedestablish a maximum administerable dose greater than 20 mg when givenonce per day, as well as confirm tolerability of a non-dose escalatingdosing regimen (i.e., administration of substantially identical doses ofmemantine throughout the term of dosing).

Purpose Multiple Dose Tolerability Dosage: 11.25, 22.5, 33.75, 45.0,56.25, 67.5, 78.75 and 90.0 mg memantine SR Concurrent Control: PlaceboRoute: Oral Subject Population: Healthy, drug-naive male subjectsStructure: Placebo-controlled, Sequential dose escalation in StudySites: Single center Blinding: Open label Method of Subject Assignment:Subjects in each Cohort will be randomized to either active drug (n =8-10) or placebo (n = 2) Total Sample Size: 80-100 subjects PrimaryEfficacy Endpoint: None Adverse Events: Monitored with reports by clinicpersonnel at least 2 or 3 times per day throughout the study, as well asvolunteered by subjects. Blood Collection Blood sampling and plasmapreparations at the following time points: Day 1: 0, 1, 2, 3, 4, 6, 7,8, 10, 12, 14, 16, 20 Days 2-6: pre-dose trough Day 7: 0, 1, 2, 3, 4, 6,7, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, 120, 144, and 168 hoursAnalysis Adverse events (including dizziness, headache, confusion,constipation, hypertension, coughing), tolerability, Pharmacokinetics

Example 20 Determination of Increased-Dose Tolerability for AmantadineSR Formulations

A study to determine safety and tolerability of increased dosing forAmantadine SR is described below. The study results are expectedestablish a maximum administerable dose greater than 200 mg when givenonce per day, as well as confirm tolerability of a non-dose escalatingdosing regimen (i.e., administration of substantially identical doses ofmemantine throughout the term of dosing).

Purpose Multiple Dose Tolerability Dosage: 100, 200, 300, 400, 500, 600,700, and 800 mg amantadine SR Concurrent Control: Placebo Route: OralSubject Population: Healthy, drug-naive male subjects Structure:Placebo-controlled, Sequential dose escalation Study Sites: Singlecenter Blinding: Open label Method of Subject Assignment: Subjects ineach Cohort will be randomized to either active drug (n = 8) or placebo(n = 2) Total Sample Size: 80-100 subjects Primary Efficacy Endpoint:None Adverse Events: Monitored with reports by clinic personnel at least2 or 3 times per day throughout the study, as well as volunteered bysubjects. Blood Collection Blood sampling and plasma preparations at thefollowing time points: Dav 1: 0, 1, 2, 3, 4, 6, 7, 8, 10, 12, 14, 16, 20Days 2-6: pre-dose trough Day 7: 0, 1, 2, 3, 4, 6, 7, 8, 10, 12, 14, 16,20, 24, 48, 72, 96, 120, 144, and 168 hours Analysis Adverse events(including dizziness, headache, confusion, constipation, hypertension,coughing), tolerability, Pharmacokinetics

Example 21 Treating NMDA-Receptor Related Disorders with ControlledRelease Formulations

A patient diagnosed with dementia of the Alzheimer's type isadministered 22.5 mg of memantine in a sustained release formulation(e.g., formulated as described in Example 13) once a day. Memantineplasma concentrations can be determined using HPLC coupled to massspectrometric detection as described in Periclou et al., Annals ofPharmacotherapy 38:1389-94 (2004). A therapeutically effective steadystate serum concentration is reached within ten days of the start ofthis therapy.

Example 22 Treating Major Depression

A patient diagnosed with Major Depression is administered 22.5 mg ormore, up to a maximum tolerated dose (as determined using the protocolin Example 20) of memantine formulated as described in Example 13, oncedaily. A therapeutically effective steady state serum concentration isreached within ten days of the start of this therapy.

Example 23 Treating Dyskinesia in Patients with Parkinson's Disease

A Parkinson's patient experiencing dyskinesia is administered a dailydose of 400 mg of a sustained released amantadine formulation.Improvements in dyskinesia are measured using UPDRS scoring.

Example 24 Clinical Trial to Compare Memantine SR Formulation toNamenda® in Patients with Alzheimer's Disease or Refractory Depression

Protocol Objective: Confirm the improvement in onset to efficacy for aQD, non-dose escalating treatment regimen Inclusion Criteria: Chosenfrom the following indications: Alzheimer's - moderate to severe ADpatients (see Tariot et al., JAMA 291: 317-24 (2004)) Refractorydepression/MADD - unresponsive to SSRIs, HamD 20-24. (see Mann N Engl JMed 353: 1819-34 (2005), Berman Biol Psychiatry 47: 351- 4 (2000),Gauthier et al., Int J Geriatr Psychiatry 20, 459-64 (2005)) Dosage:22.5 mg (20 mg delivered) Memantine SR given once per day from the onsetof therapy; Concurrent Control: 10 mg Memantine IR given twice per dayafter manufacturer's recommended dose escalation Route: Orally ortransdermally Blinding: Double blinding Total Sample Size: 120 patientsand 120 controls for each indication group Primary Efficacy Endpoint:HAMD, MADRS, NPI measured at weekly visits Secondary Efficacy Endpoint:Fatigue

In each of the above active controlled, double blind trial, the timerequired to reach a steady state plasma therapeutic level for MemantineSR is compared to that of memantine IR. Patients are screened againstthe inclusion criteria and admitted to the trial population. After a 4week washout of interfering medications, patients are scored at baselineand administered the test medication in a blinded fashion using anover-encapsulation procedure. Measurements of the endpoints are made atweekly intervals on each patient.

Based on our computer simulations, patients receiving a full dose ofMemantine SR are expected to reach steady state in 8 days, rather thanthe 40 days required in patients being administered memantine IR. Thus,beneficial effects are expected earlier in their treatment course.

Example 25 Clinical Trial to Assess Efficacy of Amantadine SRFormulation in Patients with Multiple Sclerosis

Protocol Objective: Confirm the improvement in depression,neuropsychiatric complications, and fatigue for a QD, non-doseescalating treatment regimen of amantadine Inclusion Criteria: MS -relapsing/remitting on interferon treatment with concomitant fatigue(see Bashki et al., Mult Scler 6: 181-5 (2000), Siegert et al., J NeurolNeurosurg Psychiatry 76: 469-75 (2005)) Dosage: 400 mg Amantadine SRgiven once per day from the onset of therapy. Concurrent Control:Placebo Route: Orally Blinding: Double blinding Total Sample Size: 40patients and 40 controls Primary Efficacy Endpoint: HAMD, MADRS, NPImeasured at weekly visits Secondary Efficacy Endpoint: Fatigue

In each of the above active controlled, double blind trial, AmantadineSR is compared to placebo to measure the effect. Patients are screenedagainst the inclusion criteria and admitted to the trial population.After a 4 week washout of interfering medications, patients are scoredat baseline and administered the test medication in a blinded fashionusing an overcapsulation procedure. Measurements of the endpoints aremade at weekly intervals on each patient.

Patients receiving the Amantadine SR are expected to show an improvedscore in the test criteria correlating to an improvement in depressionor fatigue.

Example 26 Clinical Trial to Assess Efficacy of Amantadine SRFormulation in Patients with Drug Induced Dyskinesia

Title: High Dose Amantadine for the treatment of Drug- InducedDyskinesia Study Phase: II Purpose This study will evaluate the effectsof amantadine on Parkinson's disease symptoms and on dyskinesias(involuntary movements) that develop as a result of long-term levodopatreatment. Amantadine inhibits the activity of glutamate which isthought to be elevated in patients with Parkinson's disease. The studyobjective is to test the hypothesis that blockade of glutamate receptorsby high doses of amantadine will lessen the severity of Parkinsoniansigns and levodopa-associated motor response complications in PDpatients to a greater extent than current amantadine doses and doseforms. Name of Drug: Amantadine SR Dosage: 400 mg QD Concurrent Control:Symmetrel (amantadine immediate release) Route: Oral Subject Population:Patients with relatively advanced Parkinson's disease and dyskinesiaswho are between 30 and 80 years of age having a URPDS-3 score of between16 and 20. Candidates are screened with a complete medical history andphysical examination, neurological evaluation, blood and urine tests,and electrocardiogram (ECG). Structure: Two arm study, treatment andplacebo arms. Study Sites: Multiple Blinding: Double blind Method ofSubject Assignment: Random Total Sample Size: 40 patients per arm StudyTerm Two weeks Primary Efficacy Endpoint: Parkinsonian symptoms andchoreiform dyskinesias are scored every 10 minutes by a maskedneurologist using an abbreviated UPDRS-3 rating scale. A modifiedabnormal movement scale (AIMS) describing involuntary movements in allextremities and trunk and face on a scale from 1-4. Secondary EfficacyEndpoints: Efficacy is assessed using validated motor function scales.Safety is monitored by means of frequent clinical evaluations andlaboratory tests. Adverse Events: Standard battery of AE assessmentscollected throughout study period Blood Collection: To determine bloodlevels of amantadine, samples are drawn intermittently throughout thestudy. Analysis: Standard assays to determine concentration ofamantadine in blood samples.

Other Embodiments

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Other aspects, advantages, and modifications arewithin the scope of the following claims.

What is claimed is:
 1. A composition comprising a modified releasecoating or matrix and an N-methyl-D-aspartate (NMDA) receptorantagonist, wherein said NMDA receptor antagonist has an in vitrodissolution profile in water that is substantially identical to its invitro dissolution profile in a dissolution medium having a pH of 1.2 andwherein said dissolution profile ranges between 0.1-20% in one hour,5-30% in two hours, 40-80% in six hours, greater than or equal to 70% in10 hours, and greater than or equal to 90% in 12 hours as measured usinga USP type II (paddle) dissolution system at 50 rpm, at a temperature of37±0.5° C.
 2. The composition of claim 1, wherein at least 95% of saidNMDA receptor antagonist in said composition is provided in a controlledrelease dosage form.
 3. The composition of claim 2, wherein at least 99%of said NMDA receptor antagonist in said composition is provided in acontrolled release dosage form.
 4. The composition of claim 3, wherein100% of said NMDA receptor antagonist in said composition is provided ina controlled release dosage form.
 5. The composition of claim 1, whereinsaid NMDA receptor antagonist is an aminoadamantine derivative.
 6. Thecomposition of claim 5, wherein said aminoadamantane derivative ismemantine, rimantadine, or amantadine.
 7. The composition of claim 6,wherein said aminoadamantane derivative is memantine.
 8. The compositionof claim of claim 1, wherein said NMDA receptor antagonist is notamantadine or dextromethorphan.
 9. The composition of claim 1, whereinsaid composition is formulated for oral, topical, transepithelial,subdermal, or inhalation delivery.
 10. The composition of claim 1,wherein said composition is formulated as a lotion or patch.
 11. Acomposition comprising a modified release coating or matrix andmemantine, wherein memantine has an in vitro dissolution profile rangingbetween 0-60% one hour, 0-86% in two hours, 0.6-100% in six hours,3-100% in 10 hours, and 8-100% in 12 hours as measured using a USP type2 (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° C.,in water.
 12. The composition of claim 11, wherein memantine has an invitro dissolution profile ranging between 0.1%-20% in one hour, 5%-30%in two hours, 40%-80% in six hours, 50% or more in 10 hours, and 90% ormore in 12 hours as measured using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C., in water.
 13. Thecomposition of claim 11, wherein at least 95% of memantine in saidcomposition is provided in a controlled release dosage form.
 14. Thecomposition of claim 13, wherein at least 99% of memantine in saidcomposition is provided in a controlled release dosage form.
 15. Thecomposition of claim 14, wherein 100% of memantine in said compositionis provided in a controlled release dosage form.
 16. The composition ofclaim 11, wherein less than 15% of memantine is released at 15 minutes.17. The composition of claim 11, wherein less than 15% of memantine isreleased at 30 minutes.
 18. The composition of claim 11, wherein atleast 60% of said memantine is released as measured at 6 hours using aUSP type 2 (paddle) dissolution system at 50 rpm, at a temperature of37±0.5° C., in a dissolution medium having a pH of 1.2.
 19. Thecomposition of claim 11, wherein said composition is formulated fororal, topical, transepithelial, subdermal, or inhalation delivery. 20.The composition of claim 19, wherein said composition is formulated as alotion or patch.
 21. A composition comprising memantine and a sustainedrelease coating or matrix, wherein the fraction of released memantine isgreater or equal to 0.01(0.297+0.0153*e^((0.515)*^(t))) and less than1−e^((−10.9)*^(t)) as measured using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C., in water, wherein t isthe time in hours and wherein t is greater than zero and equal or lessthan
 17. 22. The composition of claim 21, wherein the fraction ofreleased memantine is greater or equal to0.01(0.297+0.0153*e^((0.515)*^(t))) and less than or equal to1−e^((−0.972)*^(t)) as measured using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C., in water, wherein t isthe time in hours and wherein t is greater than zero and equal or lessthan
 17. 23. The composition of claim 21, wherein at least 95% ofmemantine in said composition is provided in an extended release dosageform.
 24. The composition of claim 23, wherein at least 99% of memantinein said composition is provided in an extended release dosage form. 25.The composition of claim 24, wherein 100% of memantine in saidcomposition is provided in an extended release dosage form.
 26. Thecomposition of claim 21, wherein less than 5% of memantine is releasedin one hour.
 27. The composition of claim 21, wherein said compositionis formulated for oral, topical, transepithelial, subdermal, orinhalation delivery.
 28. The composition of claim 21, wherein saidcomposition is formulated as a lotion or patch.
 29. A method oftreating, preventing or reducing a neurologic or neuropsychiatriccondition comprising administering to a subject at risk of having orhaving said condition a composition comprising an NMDA receptorantagonist provided in a modified release dosage form, wherein saidsubject is administered said NMDA receptor antagonist at a substantiallyidentical dose from the start of therapy.
 30. The method of claim 29,wherein said composition is the composition of any one of claims 1-28.31. The method of claim 29, wherein said condition is selected from thegroup consisting of seizure disorders, pain syndromes, neurodegenerativediseases, dementias, cerebrovascular conditions, movement disorders,brain trauma, cranial nerve disorders, neuropsychiatric disorders, otherdisease neuropathies, fatigue syndromes, ataxic syndromes, and axonicbrain damage.
 32. The method of claim 29, wherein said condition isParkinson's disease, multiple sclerosis, epilepsy, pain, depression,agitation, Alzheimer's disease, amyotrophic lateral sclerosis, orneuropathic pain.
 33. The method of claim 29, wherein said compositionis administered to said subject no more than once every 24 hours. 34.The method of claim 29, wherein said NMDA receptor antagonist reaches atherapeutically effective steady state plasma concentration in saidsubject within fifteen days of said administering.
 35. The method ofclaim 29, wherein said NMDA receptor antagonist reaches atherapeutically effective steady state plasma concentration in saidsubject within five days of said administration.
 36. The method of claim29, wherein said composition is administered to said subject no morethan once every 24 hours and wherein said NMDA receptor antagonistreaches a therapeutically effective steady state plasma concentration insaid subject in less than 30 days.
 37. The method of claim 29, whereinthe mean plasma concentration profile of said NMDA receptor antagonistin said subject has an slope from 2 hours to 4 hours afteradministration less than 50% of that for an JR formulation of the sameNMDA receptor antagonist at the same administered dose.
 38. The methodof claim 29, wherein said NMDA receptor antagonist is anaminoadamantane.
 39. The method of claim 38, wherein saidaminoadamantane is memantine, amantadine, or rimantadine.
 40. The methodof claim 39, wherein said aminoadamantane is memantine.
 41. The methodof claim 40, wherein memantine is administered at a daily dose rangingbetween 5 and 100 mg.
 42. The method of claim 41, wherein memantine isadministered at a daily dose ranging between 2 and 80 mg.
 43. The methodof claim 42, wherein memantine is administered at a daily dose rangingbetween 5 and 80 mg.
 44. The method of claim 43, wherein the daily doseof memantine ranges between 5 and 40 mg.
 45. The method of claim 43,wherein the daily dose of memantine ranges between 20 and 50 mg.
 46. Themethod of claim 45, wherein the daily dose of memantine ranges between20 and 40 mg.
 47. The method of claim 29, wherein said subject has notbeen administered said NMDA receptor antagonist, within one week ofonset of therapy, at a dose that is lower than said dose used duringtherapy.
 48. A method of preparing a pharmaceutical composition for thetreatment of a condition associated with a deregulation in NMDA receptoractivity by providing a matrix or coated core to provide sustainedrelease of a NMDA receptor antagonist, wherein said NMDA receptorantagonist is present in sufficient quantity to treat said condition,using a therapy that involves administering to a subject substantiallyidentical doses of said NMDA receptor antagonist from the onset of saidtherapy.
 49. The method of claim 48, further comprising providing amixture containing a NMDA receptor antagonist to provide an immediaterelease of a NMDA receptor antagonist, wherein the weight of saidmixture is less than 5% than the total weight of said matrix or coatedcore and mixture.
 50. The method of claim 48, wherein said NMDA receptorantagonist is memantine.
 51. The method of claim 48, wherein said NMDAreceptor antagonist is not amantadine or dextromethorphan.
 52. Themethod of claim 48, wherein said matrix core is a wax, insoluble matrixpolymer, water soluble matrix materials, or mixtures thereof.
 53. Themethod of claim 48, wherein said coated core is a core of NMDA receptorantagonist coated with a pharmaceutically acceptable polymer includingdiffusion barrier polymers with or without porosity enhancers selectedfrom the group consisting of ethyl cellulose, cellulose acetatebutyrate, cellulose acetates, polymethacrylates containing quaternaryammonium groups, polyethylene glycol, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol,and monomeric materials, sugars, lactose, sucrose, fructose andmannitol, salts, sodium chloride, potassium chloride, organic acids,fumaric acid, succinic acid, lactic acid and tartaric acid and mixturesthereof, enteric polymers, hydroxypropyl celluose, hydroxypropyl methylcellulose, polyvinyl acetate phthalate, cellulose acetate phthalate,cellulose acetate trimellitate, shellac, zein, and polymethacrylatescontaining carboxyl groups.
 54. The method of claim 48, furthercomprising compressing said core and said mixture into a tablet form andwherein said core and said mixture are dispersed throughout said tablet.55. The method of claim 48, wherein said core and said mixture arecombined and compressed into a tablet form such that said core and saidmixture form a multilayer tablet form.
 56. The method of claim 48,wherein said core and said mixture are combined into a capsule or apatch.
 57. A method of treating, preventing or reducing a neurologic orneuropsychiatric condition comprising administering to a subject at riskof having or having said condition a composition comprising an NMDAreceptor antagonist provided in a modified release dosage form, whereinsaid subject is administered said NMDA receptor antagonist at asubstantially identical dose from the start of therapy, no more thanonce every 24 hours.
 58. The method of claim 57, wherein saidcomposition is manufactured according to claim 46.